PROJECT SUMMARY/ABSTRACT Autopsy research has demonstrated that some individual who appeared to be cognitively normal in their final years had sufficient brain lesions at death to support a diagnosis of Alzheimer's disease (AD). Clearly the clinical and pathologic markers of the disease are not perfectly concordant. This phenomenon has been interpreted as implying that some individuals possess a special resilience to the cognitive decline commonly caused by the brain disease process. It suggests that clinical dementia might be prevented, delayed, or ameliorated even after the brain lesions have developed, if we could identify and cultivate those characteristics responsible for resilience. The basis of resilience could be one or a combination of several factors, including: (i) greater numbers of neurons and more extensive connectivity, (ii) a superior system of cognitive resources, including learned skills, (iii) having avoided certain aspects of the AD process, or of other structural brain disease distinct from AD that independently lead to cognitive decline and dementia. The proposed research will examine each of these alternatives in depth, employing a wealth of already available information accrued over the past 25 years of Nun Study and the Honolulu-Asia Aging Study research, plus new data to be generated with further detailed examination of Nun Study brains. Results are expected to inform the development of new and novel strategies for dementia prevention and illness amelioration.